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Abstract:

Devices and methods for treating diseases associated with loss of
neuronal function are described. The methods are designed to promote
proliferation, differentiation, migration, or integration of endogenous
progenitor stem cells of the central nervous system (CNS). A therapy,
such as an electrical signal or a stem cell enhancing agent, or a
combination of therapies, is applied to a CNS region containing
endogenous stem cells or a CNS region where the endogenous stem cells are
predicted to migrate and eventually reside, or a combination thereof.

Claims:

1. A method comprising: implanting a first therapy delivery element
comprising a therapy delivery region in a subject; positioning the
therapy delivery region of the first therapy delivery element in a first
CNS region containing endogenous stem cells selected from the group
consisting of a subventricular zone of a lateral ventricle, a central
canal of a spinal cord, a subgranular zone of the hippocamupus;
implanting a second therapy delivery element comprising a therapy
delivery region in the subject; positioning the therapy delivery region
of the second therapy delivery element in a second CNS region having
damaged neural tissue or glial cells; applying a first therapy to the
first CNS region via the therapy delivery region of the first therapy
delivery element, the first therapy configured to promote the endogenous
stem cells to proliferate, migrate, or differentiate, the first therapy
including (i) an electrical signal having a frequency of between about 1
Hz and 150 Hz, or (ii) a therapeutic agent selected from the group
consisting of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1,
NT-4, NT-5, EGF, BMP, and SCF, anti-Nogo-A antibody; and applying a
second therapy to the second CNS region via the therapy delivery region
of the second therapy delivery element, the second therapy including (i)
an electrical signal having a frequency of between about 1 Hz and 150 Hz,
or (ii) a therapeutic agent selected from the group consisting of CNTF,
GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1, NT-4, NT-5, EGF, BMP,
and SCF, anti-Nogo-A antibody, wherein the first therapy delivery element
is a catheter or a lead and the therapy delivery region of the first
therapy element is an infusion section or an electrode, wherein the
second therapy delivery element is a catheter or a lead and the therapy
delivery region of the second therapy delivery element is an infusion
section or an electrode, and wherein the first therapy and the second
therapy are the same or different.

2. The method of claim 1, wherein at least one of the first and second
therapy delivery elements is a lead.

3. The method of claim 2, further comprising implanting an electrical
signal generator in the subject and operably coupling the lead to the
electrical signal generator.

4. The method of claim 1, wherein at least one of the first and second
therapy delivery elements is a catheter.

5. The method of claim 4, further comprising implanting a pump system in
the subject and operably coupling the catheter to the pump system.

6. The method of claim 5, implanting the pump system comprises implanting
a programmable pump system.

7. The method of claim 1, wherein the first CNS region is a mediolateral
wall of a lateral ventricle.

8. The method of claim 1, further comprising delivering a growth factor
or an inhibitor of a growth inhibitory molecule intraventriculary or
intrathecally in a non-targeted manner, wherein the growth factor or
inhibitor of a growth inhibitory molecule is selected from the group
consisting of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1,
NT-4, NT-5, EGF, BMP, and SCF, anti-Nogo-A antibody.

10. A method comprising: implanting a lead comprising an electrode within
a subject; positioning the electrode in communication with a CNS region
containing endogenous stem cells selected from the group consisting of a
subventricular zone of a lateral ventricle, a central canal of a spinal
cord, a subgranular zone of the hippocamupus; implanting a catheter
comprising an infusion section within the subject; positioning the
infusion section in communication with the CNS region containing the
endogenous stem cells; applying via the electrode an electrical signal
having a frequency of between about 1 Hz and 150 Hz via the electrode to
the CNS region containing the endogenous stem cells; and applying via the
infusion section of the catheter a therapeutic agent selected from the
group consisting of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF,
IGF-1, NT-4, NT-5, EGF, BMP, SCF, and anti-Nogo-A antibody via the
infusion section to the CNS region containing the endogenous stem cells,
wherein the electrical stimulation and the therapeutic agent promote one
or more of: (a) proliferation of the endogenous stem cells; (b) migration
of the endogenous stem cells; and (c) differentiation of the endogenous
stem cells.

11. The method of claim 10, further comprising delivering a growth factor
or an inhibitor of a growth inhibitory molecule intraventriculary or
intrathecally in a non-targeted manner, wherein the growth factor or
inhibitor of a growth inhibitory molecule is selected from the group
consisting of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1,
NT-4, NT-5, EGF, BMP, and SCF, anti-Nogo-A antibody.

12. The method of claim 11, wherein the growth factor or inhibitor of a
growth inhibitory molecule is selected from the group consisting of GDNF,
BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1, CNTF, and an anti-Nogo-A
antibody.

13. The method of claim 11, wherein the electrical signal is a
depolarizing signal.

15. A method comprising: implanting a lead comprising an electrode in a
subject; positioning the electrode in a CNS region having damaged neural
tissue or damaged glial cells; implanting a catheter comprising an
infusion section in the subject; positioning the infusion section in a
CNS region containing endogenous stem cells selected from the group
consisting of a subventricular zone of a lateral ventricle, a central
canal of a spinal cord, a subgranular zone of the hippocamupus; applying
via the electrode an electrical signal having a frequency of between
about 1 Hz and 150 Hz to the CNS region; and applying via the infusion
section of the catheter a therapeutic agent selected from the group
consisting of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1,
NT-4, NT-5, EGF, BMP, and SCF, anti-Nogo-A antibody to the CNS region,
wherein the electrical signal and the therapeutic agent promote one or
more of: (a) proliferation of endogenous stem cells; (b) migration of
endogenous stem cells to the CNS region; (c) differentiation of
endogenous stem cells; and (d) integration of endogenous stem cells in
the CNS region.

16. The method of claim 15, further comprising delivering a growth factor
or an inhibitor of a growth inhibitory molecule intraventriculary or
intrathecally in a non-targeted manner, wherein the growth factor or
inhibitor of a growth inhibitory molecule is selected from the group
consisting of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1,
NT-4, NT-5, EGF, BMP, and SCF, anti-Nogo-A antibody.

17. The method of claim 15, wherein the growth factor or inhibitor of a
growth inhibitory molecule is selected from the group consisting of GDNF,
BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1, CNTF, and an anti-Nogo-A
antibody.

19. A method comprising: implanting a lead comprising an electrode in a
subject; positioning the electrode in a first CNS region containing
endogenous stem cells, wherein the first CNS region containing endogenous
stem cells is selected from the group consisting of a subventricular zone
of a lateral ventricle, a central canal of a spinal cord, a subgranular
zone of the hippocamupus; implanting a catheter comprising an infusion
section in the subject; positioning the infusion section in a second CNS
region having damaged neural tissue or damaged glia cells; applying a
first therapy to the first CNS region via the electrode of the lead, the
first therapy including an electrical signal having a frequency of
between about 1 Hz and 150 Hz; and applying a second therapy to the
second CNS region via the infusion section of the catheter, the second
therapy including a therapeutic agent selected from the group consisting
of CNTF, GDNF, BDNF, FGF, VEGF, NT-3, TGF-alpha, EGF, IGF-1, NT-4, NT-5,
EGF, BMP, and SCF, anti-Nogo-A antibody, wherein the electrical signal
and the therapeutic agent promote one or more of: (a) proliferation of
endogenous stem cells; (b) migration of endogenous stem cells to the CNS
region; (c) differentiation of endogenous stem cells; and (d) integration
of endogenous stem cells in the CNS region.

Description:

RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. application
Ser. No. 11/000,856 filed Dec. 1, 2004 which claims the benefit of
priority from provisional applications Ser. Nos. 60/526,405 and
60/526,318, both filed on Dec. 1, 2003, of which are incorporated by
reference herein in their respective entireties.

BACKGROUND

[0002] Over the past two decades, the concept of neurological tissue
grafting or exogenous stem cell transplantation has been investigated for
its potential to treat neurodegenerative disease such as Parkinson's
disease. While such transplantation approaches represent a potential for
a significant improvement over currently available treatments for
neurological disorders, there are significant drawbacks to cell
transplantation. First, ethical considerations make it difficult to
obtaining enough cells with the desired characteristics to implement
practical therapies. Upon transplantation the majority of cell types fail
to integrate with host tissue making it necessary to implant high numbers
of cells to boost the chances of integration. Furthermore, there is the
chance that the implanted cells will be immunolgically incompatibility
with the host, the transplanted cells may result in tumor formation or
pass infectious agents from the donor tissue to the host.

[0003] The presence of ongoing neurogenesis in the adult mammalian brain
raises the exciting possibility that endogenous progenitor cells may be
able to generate new neurons to replace cells lost through brain injury
or neurodegenerative disease. Several researchers have demonstrated
increased cell proliferation and the generation of new neurons in various
diseased brains. Such findings have lead to the conclusion that mitotic
activity persists in various regions of the adult mammal CNS.

[0004] Adult endogenous stem cells are activated in response to various
injuries but their capacities to proliferate, migrate, differentiate to
the appropriate cell type, make the appropriate contacts and perform the
appropriate function (ie neurotransmitter release) is quite variable.
This variability depends, in part on the lesion-type and the germinative
zone from which they arise. Various works suggest that the ability of
endogenous stem cells to proliferate, migrate, differentiate and
integrate can be enhanced by various stimulation signals. For example,
administration of growth factors and electrical stimulation have each
been suggested to promote neurogenesis and conceivably direct the
proliferation, migration, differentiation and integration of new cells in
the central nervous system. However, the method of combining several
different approaches simultaneously or in sequence, and device(s) to
achieve this has not been previously disclosed.

[0005] Deep brain electrical stimulation (DBS) has been used as therapy
for Parkisons and other disorders of the CNS including pain. Although the
mechanism of action is unknown, it is believed that DBS normalizes
aberrant neuronal cell activity. However, there is some evidence to
suggest that applying direct current electric fields can enhance the
axonal growth of a neuron (summarized in Grill et al, 2001). More
recently, two studies demonstrate that electrical activity can control
the genesis of new neurons from stem cells and control the patterns of
growth of neurons extending from the cortex to the spinal cord
(Deisseroth et al., 2004 and Salimi and Martin, 2004).

[0006] Others suggest that infusions of exogenous growth factors into the
ventricles increase the proliferation of neural progenitors around the
ventricle and the central canal of the spinal cord (Martens et al.,
2002). Furthermore, Fallon et al (2000) describe the infusion of a growth
factor to the caudate-putamen. The infusion of transforming growth factor
alpha (TGFα) resulted in the proliferation, migration and
integration of stem cells in to the substantia nigra of a 6-OHDA lesioned
rats (Fallon 2000). Growth factors are one example of a soluble
stimulation signal for neurogenesis. It is likely that a combination of
extracellular signals and microenvironmental conditions may be necessary
for the proliferation, differentiation, migration and integration of stem
cells.

[0007] Methods such as transcranial magnetic stimulation (TMS), direct and
indirect electrical stimulation have been proposed to treat a variety of
disorders and conditions. The use of electrical stimulation in these
methods is to drive the existing neurons for enhanced function.

[0008] Cell replacement therapy is another method for restoring
functionality lost to several systems of the body due to damage, disease
and or disorders of the central nervous system. Dead or dysfunctional
cells in the brain or spinal cord are replaced by undifferentiated cells,
such as stem cells or blast cells. These cells may be derived from
cultured cells, dedifferentiated cell lines, cancer cell lines, fetal
tissues or other progenitor cell types. These relatively undifferentiated
cells transform themselves to replace and assume the duties of native
cells lost due to disease, damage, or trauma. Accordingly, the implanted
cells can assume many characteristics of the native cells that they are
replacing. One method of cell replacement therapy (disclosed in U.S. Pat.
No. 6,214,334 to Lee) is to implant mature neurons at the site of nerve
damage. The mature neurons can develop as replacement cells for the
destroyed or damaged neurons and can make necessary linkages to restore
the functionality of the damaged neurons. However, the process of cell
replacement therapy does not always result in full or even partial
functionality of the replacement cells.

[0009] A method of cell replacement currently available for promoting
recovery from damage to the CNS involves implanting stem cells within the
brain or spinal cord and administering a neuronal stimulant to the cells
as described in WO01/12236 to Finklestein et al. Finklestein discloses
administering stem cells and neural stimulant in vivo to improve sensory,
motor or cognitive abilities. In one embodiment, Finklestein discloses
TMS as a neural stimulant. In another embodiment, the neural stimulant is
an anti-depressant or combinations thereof. Finkelstien dose not mention
the use of, or the administration of, growth factors, chemo-attractant
factors or other stem cell enhancing agents. Furthermore, Finkelstien
does not describe the promotion of endogenous cells for these purposes or
with these stimulants.

[0010] WO96/33731 and others in its class disclose the administration of
growth factors to promote the structural and functional integration of
implanted, exogenous neurons or grafted tissue. Here the neurotrophic
factor is administered to the CNS when the implanted neurons are
optimally responsive to the factor. WO96/33731 does not describe the
application of an electrical stimulation to promote the exogenous stem
cells.

[0011] US2003/0088274 to Gliner et al describes electrically stimulating
cells before and/or after being implanted in the nervous system of a
patient to enhance the ability of cells to achieve increased
functionality. In one aspect, Gliner describes electrically enhancing the
achievement of full functionality of cells capable of differentiating
into neurons implanted in a patient's nervous system. In another aspect,
Gilner describes electrical stimulation of fully differentiated neurons
implanted in patient's nervous system to promote growth and connectivity
of the implanted neurons. Gliner describes applying the electrical
stimulation to a defined portion of the brain where neural activity for
carrying out the neural function actually occurs in the particular
patient-usually the cortex. Gliner does not describe the use of
electrical stimulation applied to endogenous (non-implanted) stem cell or
stem cells-like populations of cell in the CNS to achieve similar
functionality. Nor does Gilner describe the administration of growth
factors, in addition to electrical stimulation to achieve functionality.

[0012] WO 95/13364 describes a method to treat a neurological disorder
caused by lost or damaged neural cells. The invention discloses the
method of administrating growth factors or genetic material to the
ventricles. The administration of such agents is intended to promote the
proliferation/differentiation and/or migration of the endogenous
precursor cells lining the ventricle so as to replace the lost or damaged
neural cells. While Wiess describes the promotion of endogenous stem
cells for replacement therapy, the delivery of growth factors and genetic
material is limited in delivery site (ventricles) and device (osmotic
pump). Additionally, WO 95/13364 and others in its class do not disclose
the use of electrical stimulation to promote the endogenous stem cells.

[0013] The aforementioned publications as well as other similar art
discloses the application of soluble stem cell enhancing agents (such as
growth factors) as well as electrical stimulation of stem cells to
promote the proliferation, migration and integration of implanted,
exogenous stem cells. However, none of the prior art mentions the
combination of the two such approaches in a step-wise or simultaneous
manner. Further, none describe or suggest the application of electrical
signals or soluble enhancing agents to more than one CNS region to
encourage proliferation, differentiation, migration or integration of
stem cells.

SUMMARY

[0014] Given the problems raised with exogenous stem cell implantation,
the current invention pertains to an improved method to promote recovery
or damaged CNS tissue by making use of the endogenous (not-implanted)
stem cells populations. The current disclosure describes devices and
methods of combining electrical and chemical therapies to optimize the
proliferation, differentiation, migration, and integration of endogenous
stem cells. In addition, this disclosure describes administration of stem
cell enhancing agents or electrical signals at more than one location to
enhance treatment of disorders associated with loss of neuronal function.

[0015] In an embodiment, the invention provides an implantable medical
device. The device comprises a housing and a pulse generator and a pump
disposed in the housing. The device further comprises a reservoir
operably coupled to the pump. The reservoir contains one or more stem
cell enhancing agents. The one or more stem cell enhancing agents promote
one or more of proliferation, migration, differentiation, and integration
of a stem cell. In an embodiment, the invention provides a system
comprising the implantable medical device, a lead, and a catheter. The
lead may be operably coupled with the pulse generator and the catheter
may be operably coupled to the pump.

[0016] An embodiment of the invention provides a method for treating a
disease associated with a loss of neuronal function in a subject in need
thereof. The method comprises implanting a first therapy delivery element
comprising a therapy delivery region in the subject, positioning the
therapy delivery region of the first therapy delivery element in a first
CNS region containing endogenous stem cells, implanting a second therapy
delivery element comprising a therapy delivery region in the subject,
positioning the therapy delivery region of the second therapy delivery
element in a second CNS region where the endogenous stem cells are
predicted to migrate and integrate, applying a first therapy to the first
CNS region via the therapy delivery region of the first therapy delivery
element, and applying a second therapy to the first CNS region via the
therapy delivery region of the second therapy delivery element. The first
therapy is configured to promote the endogenous stem cells to
proliferate, migrate, or differentiate. The second therapy is configured
to promote one or more of proliferation of the endogenous stem cells,
migration of the endogenous stem cells to the second CNS region,
differentiation of the endogenous stem cells, or integration of the
endogenous stem cells in the second CNS region cells. The first therapy
delivery element may be a catheter or a lead and the therapy delivery
region of the first therapy element may be an infusion section or an
electrode. The second therapy delivery element may be a catheter or a
lead and the therapy delivery region of the second therapy delivery
element may be an infusion section or an electrode. The first therapy and
the second therapy may be the same or different.

[0017] In an embodiment, the invention provides a method for treating a
disease associated with loss of neuronal function in a subject in need
thereof. The method comprises applying a first therapy to a first CNS
region containing endogenous stem cells, and applying a second therapy to
a second CNS region where the endogenous stem cells are predicted to
migrate and integrate. The first therapy is configured to promote one or
more of proliferation, migration, or differentiation of the stem cells.
The second therapy is configured to promote one or more of proliferation,
migration, differentiation, or integration of the stem cells. The first
therapy and the second therapy may be the same or different.

[0018] In an embodiment, the invention provides a method for treating a
disease associated with a loss of neuronal function in a subject in need
thereof. The method comprises implanting a lead comprising an electrode
within the subject, positioning the electrode in a CNS region containing
endogenous stem cells, implanting a catheter comprising an infusion
section within the subject, positioning the electrode in the CNS region
containing the endogenous stem cells, applying an electrical signal via
the electrode to the CNS region containing the endogenous stem cells, and
applying a stem cell enhancing agent via the infusion section to the CNS
region containing the endogenous stem cells. The electrical signal and
the stem cell enhancing agent are configured to promote one or more of
proliferation of the endogenous stem cells, migration of the endogenous
stem cells, or differentiation of the endogenous stem cells.

[0019] An embodiment of the invention provides a method for treating a
disease associated with a loss of neuronal function. The method comprises
applying an electrical signal to a CNS region containing endogenous stem
cells, and applying a stem cell enhancing agent to the CNS region
containing endogenous stem cells. The electrical signal and the stem cell
enhancing agent are configured to promote proliferation, migration, or
differentiation of the endogenous stem cells.

[0020] In an embodiment, the invention provides a method for treating a
disease associated with a loss of neuronal function in a subject in need
thereof. The method comprises implanting a lead comprising an electrode
in the subject, positioning the electrode in a CNS region where
endogenous stem cells are predicted to migrate and reside, implanting a
catheter comprising an infusion section in the subject, positioning the
infusion section in the CNS region where the endogenous stem cells are
predicted to migrate and reside, applying an electrical signal to the CNS
region where the endogenous stem cells are predicted to migrate and
reside, and applying a stem cell enhancing agent to the CNS region where
the endogenous stem cells are predicted to migrate and reside. The
electrical signal and the stem cell enhancing agent are configured to
promote one or more of proliferation of the endogenous stem cells,
migration of the endogenous stem cells to the second CNS region,
differentiation of the endogenous stem cells, or integration of the
endogenous stem cells in the second CNS region.

[0021] In an embodiment, the invention provides a method for treating a
disease associated with a loss of neuronal function in a subject in need
thereof. The method comprises applying an electrical signal to a CNS
region where endogenous stem cells are predicted to migrate and reside,
and applying a stem cell enhancing agent to the CNS region where
endogenous stem cells are predicted to migrate and reside. The electrical
signal and the stem cell enhancing agent are configured to promote one or
more of proliferation of the endogenous stem cells, migration of the
endogenous stem cells to the CNS region, differentiation of the
endogenous stem cells; or integration of the endogenous stem cells in the
second CNS region.

[0022] One or more embodiments of the invention provide advantages over
existing devices and methods for treating diseases associated with
diminished neuronal function. For example, the use of soluble chemical
agents and electrical signals together should prove more efficacious than
either alone for treatment of diseases associated with loss of neuronal
function. The combination of electrical signals and soluble chemical
agents should enhance the proliferation, migration, differentiation, and
integration of endogenous stem cells. The use of chemical agents or
electrical signals at more than one location in the CNS may serve to
ensure the endogenous stem cells proliferate sufficiently, migrate to the
appropriate location, differentiate, and integrate into the appropriate
location. The deficiencies of application of only electrical or only
chemical therapies at only one location may be overcome using the
description provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]FIG. 1 is a drawing of a therapy delivery system adapted to deliver
therapy to a subject's brain.

[0024] FIG. 2 is a drawing of an implantable therapy delivery system
adapted to deliver therapy to a subject's brain.

[0026] FIG. 4 is a drawing of a pump system for delivering a therapeutic
agent.

[0027] FIG. 5 is an illustration of therapeutic elements adapted to
deliver therapy to two different brain regions, one region being a source
of endogenous progenitor stem cells, the other representing a region
having damaged neural tissue.

[0028] FIGS. 6-16 are flow charts illustrating various methods for
treating a disease associated with loss of neuronal function,

[0029]FIG. 17 is a drawing of a therapy delivery device coupled to a
therapy delivery element.

[0030]FIG. 18 is a drawing of a therapy delivery device coupled to two
therapy delivery elements.

[0031]FIG. 19 is a drawing of a therapy delivery device having two
therapy delivery units, each coupled to a therapy delivery element.

[0032] The drawings are not necessarily to scale.

DETAILED DESCRIPTION

[0033] In the following descriptions, reference is made to the
accompanying drawings that form a part hereof, and in which are shown by
way of illustration several specific embodiments of the invention. It is
to be understood that other embodiments of the present invention are
contemplated and may be made without departing from the scope or spirit
of the present invention. The following detailed description, therefore,
is not to be taken in a limiting sense.

[0034] Definitions

[0035] All scientific and technical terms used in this application have
meanings commonly used in the art unless otherwise specified. The
definitions provided herein are to facilitate understanding of certain
terms used frequently herein and are not meant to limit the scope of the
present disclosure.

[0036] As used herein, "subject" means a living being having a nervous
system, to which living being a device or method of this disclosure is
applied. "Subject" includes mammals such as mice, rats, pigs, cats, dogs,
horses, non-human primates and humans.

[0037] As used herein, the terms "treat", "therapy", and the like are
meant to include methods to alleviate, slow the progression, prevent,
attenuate, or cure the treated disease.

[0038] As used herein, "disease associated with loss of neuronal function"
means a disease, disorder, condition, and the like resulting from
impairment of nervous tissue function. The impairment may result from
damage to nervous tissue, such as a neuron or glial cell. Nervous tissue
may be damaged genetically or through infection, disease, trauma, and the
like. As used herein, "repairing damaged neural tissue" means improving,
restoring, replacing the function of a damaged neuron. A neuron may be
damaged genetically or through infection, disease, trauma, and the like.

[0039] As used herein, "promoting neurogenesis" refers to a series of
events (including proliferation of a neural precursor or stem cell) that
results in the appearance of a new neuron.

[0040] As used herein, "endogenous stem cell" means stem cells that are
already present in the body. Endogenous stem cells include multipotent,
totipotent, pluripotent stem cells that are present in an organ or tissue
of a subject. Such cells are capable of giving rise to a fully
differentiated or mature cell types.

[0041] Delivery of Therapy

[0042] Referring to FIG. 17, a therapy delivery device 100 may be operably
coupled to therapy delivery element 110. A therapy delivery region (not
shown) of therapy delivery element 110 may be positioned in a subject's
centeral nervous system (CNS) to deliver a therapy. The therapy may be a
therapeutic agent or an electrical signal. Therapy delivery element 110
may be a catheter or a lead, and therapy delivery region may be an
infusion region of a catheter or an electrode.

[0043] Referring to FIG. 1, a therapy delivery region 115 of a therapy
delivery element 22 may be positioned to deliver therapy within a brain
region of a subject. Therapy delivery region 115 is shown at distal
portion of therapy delivery element 22, but it will be understood that
therapy delivery region 115 may be located at any position along
therapeutic element 22. The therapy delivery element 22 may be coupled to
a therapy delivery device 10. The device 10 may be, e.g., a signal
generator or a pump for delivering a therapeutic agent. The device 10 may
be implantable. There may be more than one therapy delivery element 22
coupled to the device 10. An individual delivery element 22 may be
divided into two portions 22A and 22B that may be implanted into the
brain bilaterally. Alternatively, a second device 10 and therapeutic
element may be used to deliver therapy to a corresponding brain region in
a second brain hemisphere.

[0044] Referring to FIG. 18, therapy delivery device 200,100 operably
coupable to two therapy delivery elements 110, 120, 22 is shown. It will
be understood that therapy delivery device 200,100 may be coupled to more
than two therapy delivery elements 110, 120, 22. As shown in FIG. 19,
therapy delivery device 200,100 may have two therapy delivery units 210,
220, which may be the same or different. For example, therapy delivery
units 210, 220 may both comprise electrical signal generators, may both
comprise pump mechanisms, or one may comprise a signal generator and one
may comprise a pump mechanism. Devices 200, 100 comprising a combination
of a electrical signal generator and an a pumping mechanism may take the
form of a device described in, e.g., U.S. Pat. No. 5,119,832, U.S. Pat.
No. 5,423,877 or U.S. Pat. No. 5,458,631, each of which are hereby
incorporated herein by reference in their entireties. It will be
understood that device 200, 100 may have more than two delivery units
210, 220.

[0045] Referring to FIG. 2, device 200, 100, 10 may be implanted in a
human body 120. The device 200, 100, 10 may be implanted in the location
shown or any other location suitable for the coupled therapeutic element
120, 110, 22 to deliver therapy to a region of the brain. Such other
suitable locations include the abdomen, the cranium, and the neck.
Therapy delivery element 120, 110, 22 may be divided into twin portions
22A and 22B that are implanted into the brain bilaterally. Alternatively,
portion 22B may be supplied with therapy from a separate element 120,
110, 22) and device 200, 100, 10.

[0046] Electrical Signal

[0047] In an embodiment of the invention, an electrical signal is applied
to a region of a subject's CNS. The CNS region may be, e.g., a brain
region having an endogenous source of neural progenitor stem cells, a
brain region to which endogenous stem cells are predicted to migrate or
integrate, a brain region to which differentiated stem cell neurons are
predicted to send projections, and the like. An "electrical signal"
refers to an electrical or electromagnetic signal. In an embodiment, the
signal has a pulse width, a frequency, an amplitude, a polarization, and
a duration. An electrical signal may be depolarizing, may be
hyperpolarizing, may increase the likelihood that a neuron will undergo
an action potential, or may decrease the likelihood that a neuron will
undergo an action potential. An electrical signal may be produced by any
means suitable for application of the signal to a region of the subject's
CNS. In an embodiment, the electrical signal is generated by a pulse
generator. The pulse generator may be implantable.

[0048] Referring to FIG. 3, a pulse generator system 300 includes a pulse
generator 310 and one or more leads 320. Any suitable pulse generator 310
and lead 320 may be used in accordance with various embodiments of the
invention. A suitable pulse generator 310 includes Medtronic Model 3625
test stimulator. A suitable lead 320 includes any of the Medtronic leads
sold with the Model 3625, such as Model YY0050931R or other custom made
leads. Lead 320 is electrically coupled to pulse generator 310. A
proximal portion 330 of the lead 320 is coupled to the pulse generator. A
distal portion 340 of the lead 320 may be positioned to apply an
electrical signal produced by a pulse generator 310 to a brain region
having an endogenous source of neural progenitor stem cells.

[0049] The pulse generator 310 may be implantable as shown for the device
10 in FIG. 2. An implantable pulse generator system 300 includes an
implantable pulse generator 310, such as Medtronic's Model 7425 Itrel or
Model 7427 Synergy. Typically, the implantable pulse generator 310 will
be electrically coupled to one or more leads 320. Suitable leads 320 are
known and can typically be purchased with implantable pulse generators
310. Examples of suitable leads 320 include Medtronic's Pisces leads,
Resume leads and other custom builds. The one or more leads 320 may be
positioned to apply an electrical signal produced by the implantable
pulse generator 310 to a brain region having an endogenous source of
neural progenitor stem cells.

[0050] A pulse generator 310, whether or not it is implantable, may be
programmed to adjust electrical signal parameters such as pulse width,
frequency, amplitude, polarization, and duration. A physician or other
person skilled in the biomedical arts with respect to neurostimulation
will understand that the parameters may be optimized to achieve an
electrical signal having desired properties. The parameters and the
location of the application of the electrical signal may be varied to
optimize therapeutic effect. In an embodiment, an electrical signal
having a voltage of between about 1 mV to about 10 mV, a frequency of
about 1 Hz to about 1000 Hz, and a pulse width of about 1 μsec to
about 500 μsec is applied to a CNS region to promote the
proliferation, differentiation, migration or integration of a stem cell.

[0051] Delivery of Therapeutic Agent

[0052] In an embodiment of the invention, one or more stem cell enhancing
agents may be administered to a CNS region of a subject. The CNS region
may be, e.g., a brain region having an endogenous source of neural
progenitor stem cells, a brain region to which endogenous stem cells are
predicted to migrate or integrate, a brain region to which differentiated
stem cell neurons are predicted to send projections, and the like. It
will be understood that therapeutic agents in addition to stem cell
enhancing agents may also be administered. The additional therapeutic
agents may be beneficial for treating a disease associated with loss of
neuronal function.

[0053] Referring to FIG. 2, a system for delivering a therapeutic agent to
a brain region of a subject is shown. The device 20 comprises a pump 40,
a reservoir 12 for housing a composition comprising a therapeutic agent,
such as a growth factor, and a catheter 38 having a proximal portion 35
operably coupled to the pump 40 and an infusion section 39 adapted for
infusing the composition to the brain region of the subject. The device
20 may be an implantable pump, as shown regarding the device 10 in FIG.
2, or may be an external pump. The device 20 may have a port 34 into
which a hypodermic needle can be inserted to inject a quantity of
therapeutic agent into reservoir 12. The device 20 may have a catheter
port 37, to which the proximal portion 35 of catheter 38 may be coupled.
The catheter port 37 may be operably coupled to reservoir 12. A connector
14 may be used to couple the catheter 38 to the catheter port 37 of the
device 20. The device 20 may contain a microprocessor 42 or similar
device that can be programmed to control the amount of fluid delivery.
The device may take the form of Medtronic's SynchroMed EL or SynchroMed
II infusion pump system.

[0054] It will be understood that a therapeutic agent may be administered
to a brain region without use of a pump system 20.

[0055] Stem Cell Enhancing Agent

[0056] In an embodiment of the invention, one or more stem cell enhancing
agent may be administered in addition to a stimulation signal. As used
herein, a "stem cell enhancing agent" is an agent that alone or in
combination with another stem cell enhancing agent or an electrical
signal increases the likelihood that a progenitor stem cell will migrate,
proliferate, differentiate, integrate or release a factor that may result
in a neural cell migrating, proliferating, differentiating, or
integrating. Stem cell enhancing agents are chemical compounds and may be
small molecule chemical agents; nucleic acids; including vectors, small
inhibitory RNA, ribozymes, and antisense molecules; polypeptides, and the
like. While some stem cell enhancing agents may affect the ability of a
cell to selectively proliferate, differentiate, migrate, or integrate, it
will be understood that many stem cell enhancing agents will affect the
ability of a cell to undergo a combination of more than one of
proliferate, differentiate, migrate and integrate. Accordingly, a
discussion of a stem cell enhancing agent as an agent that, e.g.,
promotes proliferation does not necessarily indicate that the agent may
not also promote one or more of differentiation, migration, and
integration. It will also be understood that a stem cell enhancing agent
may differentially affect proliferation, differentiation, migration, and
integration based upon the location in which the agent is administered.

[0057] A stem cell enhancing agent may be a growth factor. Any growth
factor capable of repairing damaged neural tissue and/or promoting
neurogenesis may be administered. Exemplary suitable growth factors
include glial-derived neurotrophic factor (GDNF), brain-derived
neurotrophic factor (BDNF), fibroblast growth factor (FGF), vascular
endothelial growth factor (VEGF), nerve growth factor (NGF), neurotrophin
(NT), transforming growth factor (TGF), ciliary neurotrophic factor
(CNTF), epidermal growth factor (EGF), insulin-like growth factor (IGF),
stromal cell factor (SCF), notch, heparan sulfate proteoglycans (HSPGs)
and growth factors within these classes such as, for example, NT-3,
IGF-1, FGF-2, SCF-1 and TGF-alpha. More than one growth factor may be
administered. Each growth factor may be administered in the same brain
region or may be administered in different locations. Any amount of a
growth factor may be administered. Preferably, an amount of a growth
factor capable of promoting stem cell proliferation, differentiation,
migration, or integration, when administered alone or in combination with
stimulation and/or additional therapeutic agents, is administered. It
will be understood that that the efficacy of a growth factor may be
enhanced by a cofactor. For example, administration of cofactor cystatin
C and IGF may enhance the efficacy of FGF-2. In an embodiment of the
invention, daily doses of growth factors administered are in the range of
about 0.5 micrograms to about 100 micrograms. For specific daily dose
ranges for NGF, BDNF, NT-3, CNTF, IGF-1, and GDNF that may be
administered, see U.S. Pat. No. 6,042,579, which is incorporated herein
by reference in its entirety.

[0058] Any growth factor may be administered. Some growth factors may be
referred to in the art as mitogens. In addition to the growth factors
listed above, other mitogens suitable for use in accordance with the
teachings of this disclosure include bone morphogenic proteins (BMP),
noggin, erythropoietin, and leukemia inhibitory factor (LIF).

[0059] A growth factor or other stem cell enhancing agent may be a
chemoattractant agent. A chemoattractant agent is an agent that directs a
migrating cell to a particular region or an agent that directs neuronal
projections to a particular agent. Examples of chemoattractant agents
include stromal-cell-derived factor (SCF-1), fractalkine, growth related
oncogene alpha (GRO-α), IL-8, MIP-1a, MIP-1b, MCP-1, MCP-2, MCP-3,
GRO-a, GRO-b, GRO-g, RANTES, and eotaxin

[0060] A stem cell enhancing agent may be an agent that inhibits factors
that prevent extensive cell replacement. Such agents include an anti-nogo
antibody, a p75ntr antagonist, a Rho-kinase inhibitor, and a nogo-66
receptor antagonist.

[0061] A stem cell enhancing agent may include agents that increase the
likelihood that a neuron will undergo an action potential. Such agents
include glutamate receptor agonists, such as LY 354740 or
5-dihydroxyphenylglycine (DHPG) and GABA receptor antagonists, such as
CGP56433A or bicuculline.

[0062] Other neurotransmitters and agonists of their receptors that may be
useful for promoting the proliferation, differentiation, migration, or
integration of a stem cell include norepinepherine, acetylcholine,
dopamine, serotonin, and the like.

[0063] Endogenous Source of Progenitor Stem Cells

[0064] In an embodiment of the invention, an electrical signal, a stem
cell enhancing agent, or a combination thereof is applied to a region of
the CNS having an endogenous source of progenitor stem cells. Therapy,
whether electrical or chemical, may be applied to any CNS region having
an endogenous source of progenitor stem cells. Such regions include, for
example, a subventricular zone, basal ganglia, and dentate gyms. A
subventricular zone includes a mediolateral wall of a lateral ventricle.
Dentate gyms includes hippocampus and subregions thereof. Basal ganglia
includes putamen, caudate nucleus, globus pallidus, subthalamic nucleus,
and substantia nigra. Specific germinative areas of endogenous stem cells
include the granule cell layer of the dentate gyms in the hippocampus and
the olfactory bulb. More specifically, new neurons are generated
respectively, from the subgranular zone of the dentate gyms and the
subventricular zone of the lateral ventricles. Other target stem cell
populations as suggested in the literature may include but are not
limited to the: the cortex, the fourth ventricle and the central canal of
the spinal cord, the ependymal later, hippocampus, striatum, septum,
thalamus, hypothalamus, cerebral cortex, cerebellum, retina, medial
gagnlionic eminence, optic nerve and spinal cord.

[0065] Brain Region with Damaged Tissue

[0066] In an embodiment of the invention, an electrical signal or a stem
cell enhancing agent may be applied to a region of a brain having damaged
neural tissue or damage to the glial cells. An electrical stimulation
signal or a stem cell enhancing agent may be applied to any brain area
having damaged neural tissue. In an embodiment, a therapy (i.e,
electrical signal, stem cell enhancing agent, or combination thereof) is
applied to a brain region having an endogenous source of progenitor stem
cells and a brain region having damaged neural tissue.

[0067] Damaged neural tissue may arise from a genetic source, a disease,
and/or a trauma. Damaged neural tissue may result from a
neruodegenerative disease, such as Parkinson's disease and Alzheimer's
disease. In Parkinson's disease, damage neural tissue may be found in the
substantia nigra. In Alzheimer's disease, damaged neural tissue may be
found in the basal forebrain, particularly the nucleus basalis of
meynert, or the hippocampus, specifically the CA1 region. In a condition
such as spinal cord injury, it may be desirable to administer a therapy
to intrathecally at or near the level of the injury. Damaged neural
tissue will be readily identifiable to a physician or other persons
skilled in the biomedical arts.

[0068] Brain regions having damaged neural tissue may be the same or
different from brain regions having an endogenous source of progenitor
stem cells.

[0069] One exemplary therapy includes the administration of the growth
factor, TGF-alpha, at a dose and rate sufficient to encourage
proliferation, differentiation, migration, or integration. A suggested
rate is in the range from about 0.2 μl/day to about 24 μl/day. A
suggested dose is in the range from about 0.1 mg/ml to about 100 mg/ml.

[0070] Another exemplary therapy includes the administration of noggin and
BMP. Temporally and spatially controlled administration of BMP and noggin
may be achieved using a device(s) as described herein or as known in the
art. Exogenous noggin may be delivered to the ependymal cells to promote
neuronal differentiation whereas exogenous BMP may be delivered to the
same area to promote glial differentiation.

[0071] Another exemplary therapy includes applying an electrical signal to
promote the expression of an endogenous gene product at parameters
sufficient to encourage the proliferation, differentiation, migration or
integration of an endogenous stem cell. For example, the endogenous
expression of c-fos, neuroD2, nogging, or various other stem cell
enhancing agents may be encouraged. Electrical signal parameters may be
in the range from, e.g., about 1 Hz to about 150 Hz, about 90 μsec to
about 500 μsec, and about 0.1 V to about 10V.

[0072] In addition to delivering a stem cell enhancing agent to a CNS
region comprising damaged neural tissue, it may be desirable to deliver
such agents intraventricularly or intrathecally. Such non-targeted
delivery of therapy may broadly encourage the proliferation or migration
of stem cells.

[0073] Brain Regions to which Neurons Project

[0074] In an embodiment, therapy is delivered to a CNS region in which
neurons are predicted to project. More particularly, therapy may be
administered to a region where differentiated neuronal stem cells are
expected to project to facilitate the newly developed or existing yet
damaged neurons to make the appropriate neuronal connections.

[0075] Regions to which neurons are expected to send projections are known
to those of skill in the art. For example, neurons of the substantial
nigra send projections to the putamen. Accordingly to treat Parkinson's
disease, it may be desirable to encourage newly integrated or
differentiated neurons or damaged neurons of the substantia nigra to send
projections to the putamen. This may be accomplished by delivering
electrical signal, a stem cell enhancing agent, or a combination thereof
to the putamen to encourage the neurons of the substantia nigra to make
appropriate connections with neurons of the putamen.

[0076] In another example, a group of cholinergic neurons in the basal
forebrain project to the neocortical and medial temporal regions. In
Alzhiemer's disease this group of cholinergic neurons are selectively
damaged, resulting in severe impairment of learning. It may be desirable
to encourage newly integrated or differentiated neurons of the basal
forebrain to send projections to the neocortical and medial temporal
regions. Furthermore, it may be desirable to encourage the newly
established neuronal cell to produce acetylcholine to restore the
function of the cholinergic transmission in the brain area. This may be
accomplished by delivering electrical signal, a stem cell enhancing
agent, or a combination thereof to the neocortical and the medial
temporal regions to encourage the neurons of the basal forebrain to make
appropriate connections with neurons of the neocortical or medial
temporal region. Likewise, replacement strategy may be achieved by
delivering electrical signal, a stem cell enhancing agent, or a
combination thereof to the basal forebrain to encourage the neurons of
the neocortical and medial temporal regions to make appropriate
connections with neurons of the basal forebrain.

[0077] Other neurotransmitter systems are selectively disrupted by the
Alzheiemer's disease process in a manner similar to the cholinergic
system. In another example, the cortically projecting norepinephrine
neurons of the locus coeruleus and the raphe neurons of the dorsal and
central raphe nuclei are disrupted. It may be desirable to encourage
newly differentiated or integrated or damaged neurons of the locus
coeruleus and the raphe nucleus to send projections to the cortex. This
may be accomplished by delivering electrical signal, a stem cell
enhancing agent, or a combination thereof to the locus coeruleus and the
raphe nucleus.

[0078] In another example, axons of the neurons in the spinal cord may
traverse some distance in the spinal cord on their way to project to a
particular spinal cord level. During spinal cord injury, these axonal
projections are damaged, resulting in impairment of sensory and movement
functions and often paralysis. It may be desirable to encourage the newly
integrated or differentiated neurons of one spinal cord level to send
projections to the other spinal cord level in a manner that will result
in an the repair of axonal projections over the injured area.

[0079] Therapy

[0080] In various embodiments of the invention, therapy may be delivered
to one or more CNS regions to treat a disease associated with loss of
neuronal function. One or more therapies, e.g. electrical signal and stem
cell enhancing agent, may be delivered to, e.g., one or more of an
endogenous source of progenitor stem cells, a region comprising damaged
neuronal tissue, or a region to which neurons project. In various
embodiments, a stem cell enhancing agent is delivered to two or more of
such regions. In various embodiments, electrical signals and stem cell
enhancing agents are delivered to one or more of such regions. For
example a stimulation signal and a stem cell enhancing agent may be
delivered to the same CNS region or may be delivered to different CNS
regions.

[0081] An embodiment of the invention provides a method for treating a
disease associated with loss of neuronal function, where therapy is
directed to a brain region having an endogenous source of progenitor stem
cells and a brain region having damaged neural tissue. Therapy may be
application of an electrical signal or delivery of a stem cell enhancing
agent. Therapy may be applied to any brain region having an endogenous
source of progenitor stem cells and any brain region having damaged
neural tissue.

[0082] Referring to FIG. 5, an exemplary embodiment is shown where an
electrical signal is applied and a stem cell enhancing agent is
delivered. As shown in FIG. 5, a catheter with an electrode 5 may be
positioned in a region containing endogenous stem cells. The catheter
with an electrode 5 is positioned at the lateral walls of the ventricles.
At step 1, a stem cell enhancing agent may be delivered via the catheter
with the electrode 5 to the lateral walls of the ventricles. At step 2,
an electrical signal may also be applied to the lateral walls of the
ventricles. As shown in FIG. 5, a catheter 6 may be placed to deliver a
stem cell enhancing agent at a location containing damaged nervous
tissue. In the example provided by FIG. 5, the catheter 6 is positioned
to deliver the stem cell enhancing agent to the substantia nigra. At step
3, a chemoattractant stem cell enhancing agent is delivered to the
substantia nigra to draw stem cells to the targeted CNS region.

[0083] Referring to FIG. 6, an overview of a method of treating a disease
associated with a loss of neuronal function is shown. As shown in FIG. 6,
a first therapy may be delivered to a first area of the CNS containing
endogenous stem cells (1000). As shown in FIG. 7 at 1020, the therapy may
be an electrical signal or a stem cell enhancing agent. A second therapy
is applied to a second area of the CNS where the endogenous stem cells
are predicted to migrate and eventually reside (1010). As shown in FIG. 7
at 1030, the therapy may be an electrical signal or a stem cell enhancing
agent. The first and second therapy may be the same or different.

[0084]FIG. 8 refers to a method of achieving the treatment protocol as
described in FIG. 6 or 7. An infusion section of a first catheter or a
first electrode is positioned in a first area of the CNS containing
endogenous stem cells (1040), and an infusion section of a second
catheter or a second electrode is positioned in a second area of the CNS
where the stem cells are predicted to migrate and eventually reside
(1050). An electrical signal or stem cell enhancing agent is then applied
to the first area of the CNS (1060) and the second area of the CNS
(1070). As shown in FIG. 9, a stem cell enhancing agent may be delivered
intraventricularly or intrathecally in a non targeted manner to enhance
the treatment of the disease (1080). FIG. 10 depicts a method for
carrying out the treatment protocol of FIG. 9. At 1090 a catheter an
infusion section of a catheter is positioned into a cerebral ventricle or
into the intrathecal space, and at 1100 a stem cell enhancing agent is
delivered intraventricularly or intrathecally via the catheter.

[0085] Referring to FIG. 11, an overview of a method of treating a disease
associated with a loss of neuronal function is shown. As shown in FIG.
11, an electrical signal (1110) and a stem cell enhancing agent (1120)
may be delivered to an area of the CNS containing endogenous stem cells.
FIG. 12 depicts a method of achieving the treatment protocol as described
in FIGS. 11. At 1130 an electrode is positioned in an area of the CNS
containing endogenous stem cells. At 1140 an infusion section of a
catheter is positioned in an area of the CNS containing endogenous stem
cells. An electrical signal (1150) and a stem cell enhancing agent (1160)
is applied to the area of the CNS.

[0086] Referring to FIG. 13, an overview of a method of treating a disease
associated with a loss of neuronal function is shown. As shown in FIG.
13, an electrical signal (1170) and a stem cell enhancing agent (1180)
may be delivered to an area of the CNS where endogenous stem cells are
predicted to migrate and eventually reside. FIG. 14 depicts a method of
achieving the treatment protocol as described in FIGS. 12. At 1190 an
electrode is positioned in an area of the CNS where endogenous stem cells
are predicted to migrate and eventually reside. At 1200 an infusion
section of a catheter is positioned in an area of the CNS where
endogenous stem cells are predicted to migrate and eventually reside. An
electrical signal (1210) and a stem cell enhancing agent (1220) is
applied to the area of the CNS.

[0087] Referring to FIG. 15, an overview of a method of treating a disease
associated with a loss of neuronal function is shown. An electrical
signal is applied to an area of the CNS containing endogenous stem cells
(1230), a stem cell enhancing agent is delivered to the area of the CNS
containing endogenous stem cells (1240), and a stem cell enhancing agent
is delivered intraventricularly or intrathecally (1250).

[0088] Referring to FIG. 16, an overview of a method of treating a disease
associated with a loss of neuronal function is shown. An electrical
signal is applied to an area of the CNS where endogenous stem cells are
predicted to migrate and eventually reside (1260), a stem cell enhancing
agent is delivered to the area of the CNS where endogenous stem cells are
predicted to migrate and eventually reside (1270), and a stem cell
enhancing agent is delivered intraventricularly or intrathecally (1280).

[0089] Other methods and combinations of steps shown in FIGS. 6-16 are
contemplated. It will be understood that various steps as shown in FIGS.
6-16 may occur in any logical order and applications of various therapies
can occur at the same or different times.

[0090] All printed publications, such as patents, patent applications,
technical papers, and brochures, cited herein are hereby incorporated by
reference herein, each in its respective entirety. As those of ordinary
skill in the art will readily appreciate upon reading the description
herein, at least some of the devices and methods disclosed in the patents
and publications cited herein may be modified advantageously in
accordance with the teachings of the present invention.

Patent applications by Lisa L. Shafer, Stillwater, MN US

Patent applications by MEDTRONIC, INC.

Patent applications in class Combined with nonelectrical therapy

Patent applications in all subclasses Combined with nonelectrical therapy